Conducting clinical trials in five Eastern European countries (EU-EECs) with a focus on Bulgaria

Abstract

Data for ongoing and completed clinical trials (Phases I-III) were extracted from the European Union Clinical Trials Register for five EU-EECs (Bulgaria, Hungary, Poland, Romania and Slovakia) (from January 1, 2012 to September 30, 2022). Based on the almost 11-year period Poland (n = 4134) and Hungary (n = 3845) represent the largest share of trials, with over 250–300 ongoing and completed clinical trials a year. Bulgaria (with a population of 7 mill. inhabitants) has a lower number of completed and ongoing trials (n = 2049) versus Poland and Hungary, which, however, have much larger populations (Poland − 38 mill., Hungary − 9.8 mill.). Slovakia (5.5 mill. inhabitants), has 67% fewer ongoing and completed clinical trials (n = 1374) than Poland, while Hungary and Bulgaria also have more trials than Slovakia (64% and 33% respectively). The prevalence of trials in all EEC countries was calculated per 100,000 inhabitants, where Hungary (n = 39) ranks first, while Bulgaria (n = 29) is ahead of Slovakia (n = 25), Poland (n = 11) and Romania (n = 5). The ongoing and completed clinical trials conducted in the ten EU-EECs (n = 19030) have shown remarkable expansion over the past decade, accounting for a large share (26.3%) of all EU-wide trials (n = 72215) for the referenced period. The leader of the western EU countries, in terms of trials per 100,000 inhabitants is Denmark (n = 56) followed by Belgium (n = 44), Austria (n = 33), Finland (n = 30) and the Netherlands (n = 30). These results demonstrate that the number of completed and ongoing trials does not correspond to the size of a country’s population.

Keywords:

• Clinical trials register
• completed and ongoing clinical trials
• regulatory requirements
• rare disease indication
• distribution by clinical trial phase

Introduction

The rapid rise of globalization, combined with the high costs of clinical research, and the urgent need for innovation, has led to an increase in cross-country competition regarding costs, speed of patient recruitment, and the availability of patient population and qualified clinical research professionals.

Rapid economic growth and improved regulatory processes in the emerging and growing regions of the European Union - Eastern European Countries (EU-EECs), driven by broader adoption of the European Medicines Agency (EMA) and International Council for Harmonisation (ICH) guidelines and the implementation of the new Regulation (EC) 536/2014, are the essential competitive factors vis-à-vis the United States and other regions. Biopharmaceutical and biotechnology companies have thus detected new opportunities in the European Union (EU) and the EU-EECs, where clinical trial data are systematized in an EU clinical trial register [1–4].

Over the last 20 years, the adoption of EU clinical trials legislation by EU-EECs, particularly by Bulgaria, has resulted in a significant increase in the region’s importance in multinational clinical trials, [5, 6]. Furthermore, introducing Directive 2001/20/EC in the EU in 2004 and Bulgaria in 2007 stimulated sponsors’ interest in conducting clinical trials in this region [7, 8].

This study aims to analyze the clinical trial environment in the EU-EECs and the benefits of conducting clinical trials in order for more patients to have access to innovative therapies, and for sponsors recruit patients fasters in this region, focusing on Bulgaria.

Materials and methods

Documentary method

This study was based on examining and acquiring legislative documents, EU regulations, EU directives, publications, and reports of local and EU requirements on conducting clinical trials.

Analytical and comparative methods

The statistical clinical trial data extracted from the EU Clinical Trials Register for Bulgaria, Hungary, Poland, Romania and Slovakia were analyzed based on the following indicators: total number of ongoing and completed clinical trials (Phase I-III, Interventional trials), the prevalence of rare disease trials, distribution by phase and completed ongoing trials in the EU-EECs and all EU Member States (MSs).

Historical method

Data were analyzed for a period of over nearly eleven years (from 1 January 2012 to 30 September 2022) in clinical trials in five EU-EECs (Bulgaria, Romania, Slovakia, Poland and Hungary) and all other EU MSs.

Empirical method and comparative analysis

Analysis was based on data collected from various sources, including articles, EU regulations, EU directives, guidelines, the EU Clinical Trials Register website, and the competent authorities of the EU-EECs.

Graphical representation

The results of the examined EU-EECs were illustrated in charts for easier comparison, discussion and analysis.

Materials

The study was based on data from the EU Clinical Trials Register from 1 January 2012 to 30 September 2022. Publicly available data from competent authorities (performance metrics, annual reports and statistics) on annually submitted clinical trial applications (CTAs) (Phase I-III) were compiled, and the distribution of completed and ongoing trials, the prevalence of clinical trials per 100,000 inhabitants, using EUROSTAT data were collected in October 2022 for all EU countries (Inhabitants: Bulgaria − 7 mill., Hungary − 9.8 mill., Poland − 38 mill., Romania − 19.3 mill., and Slovakia − 5.5 mill.). Clinical trial distribution by Phase (I-III) as well as for rare diseases studies were systematized. In addition, pediatric clinical trials were also monitored. Under the relevant figures, the date of accessing the EU Clinical Trials Register is specified as October 2022. For pediatric studies the following indicators were used from the EU Clinical Trials Register: children, in utero, infant and toddler, new-born, preterm new-born infants, under 18.

Results

Regulatory landscape and impact of Directive 2001/20/ЕC in the EU

Directive 2001/20/EC of 4 April 2004, was the critical legislative document governing clinical research in the Union, resulting in revisions and modifications to the national laws, ordinances, and administrative provisions of EU MSs. The implementation of GCP ICH E6 in the EU-EECs began prior to the 2004 accession of the first EU-EECs. The Directive had to be implemented in Bulgarian law until the end of 2007 once the country joined the EU [1, 8, 9].

Implementing the Clinical Trials Directive 2001/20/EC (CTD) has significantly increased clinical trials data safety, ethical aspects, quality, and reliability in the EU. On the other hand, the CTD curbed the competitiveness of the EU as a location for conducting clinical trials and drug development, primarily due to an increasing administrative burden and rising costs of EU clinical trials [8].

According to the EU Commission’s Impact on Clinical Research of European Law (ICREL) initiative, the approval process of clinical trials in the EU remained unchanged after implementing Directive 2001/20/EC. Nevertheless, conducting such trials has become increasingly complex and expensive. Several independent assessments of the same clinical trial across the EU resulted in diverse decisions by the competent authorities and ethic committees in various EU MSs, in spite of evaluating the same documents. Other types of clinical trials (such as non-interventional studies) were also subject to different requirements across the EU MSs. Lack of standardization has a considerable negative impact on the landscape of the conduct of global clinical trials. It has raised concerns over EU’s competitiveness and attractiveness for clinical research, including registration trials with new medicines, trials comparing treatment methods utilizing commercially available medications, and minimally invasive trials. Subject matter experts and academic institutions conducting non-commercial research, in particular, have faced significant challenges in carrying out their responsibilities to their sponsors [8, 10, 11].

Regulatory analysis of clinical trials conducted in the EU-EECs (comparison between Bulgaria, Romania, Poland, Hungary and Slovakia)

The five countries in this part of the analysis (Bulgaria, Romania, Poland, Hungary and Slovakia) are all members of the EU and, as such, have common clinical trials legislation. The CTD, a critical legal act governing the conduct of clinical trials in the EU, is Directive 2001/20/EC, which sought to harmonize clinical trials rules across EU Member States and facilitate drug development. [8]

The CTD requirements are implemented in the national legislation of all EU-EECs even if the implementation does not always run as intended. The following requirements differ throughout the countries studied:

• Regulatory timelines (the official assessment timeline in Hungary is 75 days with no clock stop option, 60 days for Bulgaria) [9, 12].

• Requirements for documents in local language (Application Forms, Informed Consent, Labels, Patient facing materials). Various settings of documents to competent authorities and ethics committees (around 10-15 documents in Slovakia compared to significantly more in Bulgaria – 44) [13, 14].

• Certain countries, such as Romania, suffer severe regulatory assessment delays (301 days on average in 2019 versus 60 days as by law) [15].

Any regulatory differences in the clinical trials conduct in the EU as described above should be eliminated. The local requirements should be harmonized with the EU Clinical Trial Regulation full implementation. [2] As of February 1, 2023, all new studies have to be submitted through the new EU Clinical Trials Information System (CTIS), with identical Part I and specific Part II dossiers for each Member State [16].

The Clinical Trials Regulation will standardize the clinical trial submission, evaluation, timelines and oversight across the EU. Sponsors can register for a clinical trial in up to 30 EU/EEA countries through a single application that includes submissions to competent national authorities, ethics committees and public registration of the clinical trial. As soon as clinical trial applications are filed through the system, Member States and EU-EECs will begin working in CTIS. Sponsors may have submitted initial clinical trial applications under the Clinical Trials Regulation (through CTIS) or the CTD up until January 31, 2023. However, all ongoing clinical trials must be transitioned to EU Regulation 536/2014 by 31 January 2025 [16, 17].

The clinical trial regulatory environment in Bulgaria for the period 1995–2022

The first law in Bulgaria regulating clinical trials was the Drugs and Pharmacies in Human Medicine Act in 1995. Adopting CTD 2001/20/EC led to significant revisions in clinical trials in 2007. [8, 18].

After implementing the the Drugs and Pharmacies in Human Medicine Act in 1995, the number of clinical trials in Bulgaria rose from 88 in 1999 to 175 in 2006, a 52% increase. In subsequent years, the number of clinical trials increased steadily (Figure 1) [5, 6].

Figure 1. Clinical trials in Bulgaria 1995–2021 (source BDA reports) [5].

After the ICH GCP implementation in 2001 and Bulgaria’s accession to the EU in 2007, the regulatory environment for clinical trials in Bulgaria gradually improved. In April 2007, Directive 2001/20/EC was incorporated into the new Medicinal Products in Human Medicine Act [9] and the Clinical Trials Ordinance 31 of the Bulgarian Ministry of Health [20]. Initiating clinical trials in Bulgaria, implementing the EU CTD, required submitting numerous pieces of paperwork to the responsible competent authorities and ethics committees to comply with GCP. Before submitting a proposed clinical trial in Bulgaria, an entirely executed contract was required by law, which significantly slowed down the submission process. The amendments to Ordinance 31 that took effect in 2016 had a positive effect on the approval process for clinical trials in Bulgaria and sponsors were no longer required to submit fully signed contracts along with their initial clinical trial application to the competent authorities (CA), the Bulgarian Drug Agency (BDA) and Ethics Committees. A sub-investigator replacement was no longer regarded as a substantial amendment following a key change in the Bulgarian Medicinal Products in Human Medicine Act. Many more examples and other regulatory issues were addressed to improve the overall domain of clinical trials in Bulgaria, which has been attracting an increasing number of stakeholders during the last decade [6, 8, 19, 20].

The Bulgarian clinical trials legislation was overhauled in 2018 in accordance with Regulation (EC) 536/2014 in order to apply all European regulatory rules pertaining to CTIS, transparency of clinical trial procedures, and safety [2, 9].

Despite the COVID-19 pandemic, 200 new clinical trials were initiated in Bulgaria in 2020 and 2021. The above data show the landscape for novel molecule research and the evolution of clinical trials in Bulgaria since 1995, after the first legal requirements were enacted. Ever since Bulgaria’s accession to the EU in 2007, the number of clinical trials has expanded significantly, with an average annual number of 214 trials over the past decade. It is representative of the competitive and favorable landscape that Bulgaria presents to sponsors for conducting their clinical trials.

To support and attract sponsors, the Bulgarian Drug Agency (BDA) published local guidance on the document requirements for Part II based on Regulation (EC) 536/2014 of the clinical trial dossier, further detailing requirements of the expected national language documents [17].

Analysis of the phases of completed and ongoing clinical trials in the five EU-EECs

In this study, we compared the prevalence of different clinical trials in the five studied EU-EECs including Bulgaria, Hungary, Poland, Romania and Slovakia.

Throughout the reference period (from 1 January 2012 until 30 September 2022), clinical trials data for the five EU-EECs were extracted from the EU Clinical Trials Register and analyzed [4]. The data were analysed based on several indicators, such as the total number of completed and ongoing clinical trials, study phase distribution, the amount of pediatric studies and the prevalence of rare disease studies and were compared across the countries of the selected region [4].

EU-EECs were selected for the study on the basis of a similar gross domestic product (GDP) per capita, close geographical regions, and equal EU regulatory and clinical trial requirements, regardless of the population size [12–15, 21].

On the basis of nearly eleven years of ongoing and completed clinical trial data, Poland (n = 4134) and Hungary (n = 3845) represent the largest share, with about 250–300 clinical trials a year in each country. Apparently, Bulgaria has a lower number (49.5% and 47% less, respectively) of completed and ongoing trials (n = 2049) versus Poland and Hungary. It is important to stress that Hungary accounts for only 7% less trials than Poland despite the latter having an almost four times larger population and, hence, higher potential for more participants. Bulgaria has a leading place among the five examined countries in clinical trials when the country population is taken into account. [22] Slovakia’s completed and ongoing studies (n = 1374) when taking into account the population account for less (67%) than Poland. Hungary and Bulgaria both have more trials (64% and 33% respectively) than Slovakia, which accounts for 36% more trials than Romania (n = 901). This shows that the number of completed and ongoing trials does not correspond to the country population, indicating that many other factors have to be considered. (Figure 2)

Figure 2. Cumulative number of completed and ongoing clinical trials from 1 January 2012 to 30 September 2022 (Phases I, II, III) [4].

To provide a more accurate picture of the prevalence of clinical trials in the countries analyzed, the number of completed and ongoing trials per 100,000 inhabitants was calculated (based on EUROSTAT data), and the results were summarized. Hungary (n = 39) is in the forefront, and Bulgaria (n = 29) is ahead of Slovakia (n = 25), Poland (n = 11) and Romania (n = 5). Based on these parameters, the number of sponsored trials per capita is higher in Hungary and Bulgaria [22] (Figure 3).

Figure 3. Number of clinical trials per 100,000 inhabitants, completed and ongoing for the period of 1 January 2012 until 30 September 2022 (Phases I, II, III) [4, 22].

The initial analysis examined the total number of completed clinical trials, and the top three countries in terms of prevalence are Poland, Hungary and Bulgaria, with Hungary having the largest number of completed trials (n = 2404) and Poland having only 0.2% fewer (n = 2399). The results for Romania (n = 514) and Slovakia (n = 932) favour Bulgaria, which has 62% and 30% respectively more completed (n = 1337) and ongoing clinical trials (n = 712), despite the larger population in Romania (19.3 mill. Inhabitants) (Figure 4).

Figure 4. Distribution of completed and ongoing clinical trials for the period from 1 January 2012 until 30 September 2022 (Phases I, II, III) [4].

Phases I, II and III of the completed and ongoing clinical trials in the selected five EU-EECs were analyzed and evaluated [4]. Figure 5 displays the distribution of Phases I, II and III of completed and ongoing clinical trials in the five EU-EECs for the period from January 1, 2012 until 30 September 2022. The phase distribution is dominated by Phase III trials in all five EU-EECs, followed by Phase II and Phase I and that distribution is consistent across all five countries included in the analysis. (Figure 5) The proportion of Phase III studies allocated by sponsors to countries ranges from 62.1% (Poland) to 73.6% (Slovakia), with Bulgaria (67.6%) ranking third among the five EC-EECs. As these trials are used as evidence in the marketing authorisations files, this indicates that the pharmaceutical industry has high trust in the quality of data that these three countries generate.

Figure 5. Distribution of Phases I, II and III of completed and ongoing clinical trials in the five EU-EECs for the period from 1 January 2012 until 30 September 2022 (presented as %) [4].

Phase II trials, range from 24.7% (Slovakia) to 33.3% (Poland) and the prevalence of Phase I trials goes from 1.7% (Slovakia) to 4.3% (Poland). The low number of Phase I studies could be attributed to the fact that these studies involve a small number of patients and are performed in a few specialised centers and regions to ensure the proper study oversight. The multiregional, multicenter Phase I studies are rather rare, even though they have become more and more popular in recent years with the increasing use of the multi-arm complex clinical trials.

Similar to the other countries studied, the landscape of clinical trials in Bulgaria is diverse, based on roughly eleven years of available data.

Analysis of completed and ongoing clinical trials with rare disease indications and pediatric patients in the five EU-EECs

Finding patients with rare diseases is considered to be one of the key challenges in the clinical trial industry all over the world. The conduct of trials in pediatric patients might also pose a challenge, since children are regarded as vulnerable subjects for research, which should proceed only if the trial does not involve more than minimal risk and there is the prospect of direct clinical benefit to the subject. Therefore, these types of trials were also subject of this survey with the goal to determine the available experience, if any, in the selected EU-EECs. Figure 6 shows the number of completed and ongoing pediatric studies and clinical trials in rare disease indications over the examined 11-year period in the five EU-EECs surveyed.

Figure 6. Distribution of completed and ongoing clinical trials (Phases I, II and III) in the five EU-EECs from 1 January 2012 to 30 September 2022, of rare disease indications and in pediatric patients [4].

There is a substantial difference between the number of completed and ongoing trials in the five countries reviewed. The most pediatric trials are in Poland (n = 776) and Hungary (n = 551), 29% less than in Poland. Bulgaria accounts for less than they do (n = 314) while the rest of the surveyed countries, Slovakia (n = 195) and Romania (n = 139), account for 38% and 56% less, respectively. (Figure 6)

Considering the population size differences in the surveyed countries, the percentage of completed and ongoing pediatric clinical trials in the studied countries ranges from 5.62 in Hungary to 0.72 in Romania. Bulgaria ranks second (4.49) and Slovakia third (3.55) for trials per 100,000 inhabitants. Apparently, the wide range of morbidity in that age group, qualified professionals, and limited access to the most cutting-edge innovative medicinal products for many disabilities and life-threatening conditions in children of various ages, leads to a high number of clinical trials in pediatric studies in that region (Figure 7) [4].

Figure 7. Total number of completed and ongoing clinical trials (Phases I, II and III) with rare disease indications and with pediatric patients from 1 January 2012 until 30 September 2022 [4].

The analysis of the total number of clinical trials with rare disease indications conducted during the same 11-year period in the five countries showed that in terms of total number of trials performed, Bulgaria ranks third (n = 240) despite having a substantially smaller population than Poland (n = 687) and Hungary (n = 517) (Figure 6).

For the nearly 11-year period studied, rare disease indications accounted in Poland for 16.6% and in Hungary for 13.4% of all ongoing and completed clinical trials. The rest of the countries, Romania 12.2% (n = 111), Bulgaria 11.7% (n = 240) and Slovakia 8.5% (n = 117) have also experienced similar rare disease indications.

When the data are presented per 100,000 inhabitants, Hungary (n = 5.28) and Bulgaria (n = 3.43) show the best results followed by Slovakia (n = 2.13), Poland (n = 1.81) and Romania (n = 0.58) (Figure 7).

Completed and ongoing clinical trials in all EU MSs from 1 January 2012 until 30 September 2022 as a baseline for the five surveyed EU-EECs

During the 1990s, political changes encouraged the international integration of clinical research in the EU, and today, multiple trials have attracted partners from the entire continent. Many publications emphasize the history and current situation of international cooperation in conducting clinical trials in Central and Eastern Europe, which began at the end of the 1990s into the beginning of the next decade [23–32].

To analyze the clinical trials in the five EU-EECs surveyed and establish a baseline for them, we decided to compare the selected five EU-EECs with the remaining EU MSs. We extracted data for all EU MSs for completed and ongoing clinical trials from 1 January 2012 until 30 September 2022, and provided it as the overall number of trials and the number of trials per 100,000 inhabitants using the EUROSTAT data for each country. (Figures 8 and 9) [4, 22].

Figure 8. Total number of completed and ongoing clinical trials (Phases I, II and III) in all EU Member States from 1 January 2012 until 30 September 2022 [4].

Figure 9. Completed and ongoing clinical trials (Phases I, II and III) per 100,000 inhabitants in all EU Member States [4].

Within the same timeframe, there were 19,030 clinical trials in all EU-EECs (Poland, Czech Republic, Bulgaria, Slovakia, Romania, Lithuania, Latvia, Estonia, Croatia), representing 26.3% of all completed and ongoing clinical trials in the EU. The most clinical trials were conducted in Poland (21%), Hungary (20%), the Czech Republic (18%) and Bulgaria (10%), among the ten EU-EECs. (Figure 8). For the last ten years, the completion of clinical trials in EU-EECs has improved drastically, compared to the situation in 2010, when the percentage of clinical trials conducted in this region from all clinical trials in the EU was only 12–13% [6, 33, 34]. According to surveys (2010 and 2014), Central and Eastern Europe increased its global biopharmaceutical-sponsored clinical trial sites market share to 12.5-13.6%, with a relative solid market growth of 12.2%, keeping its position as a top destination among emerging markets by a large margin [6, 35].

Older EU MSs, namely Spain (n = 8105; 11%), Germany (n = 7903; 10.9%) and Italy (n = 7477; 10.3%), account for the largest number of ongoing and completed clinical trials in all EU MSs (n = 72215). This is due to the fact that the majority of innovative industries and clinical research traditions are still located in these countries (Figure 8).

From January 1, 2012 until September 30, 2022, a total of 72,215 ongoing and completed clinical trials were performed in all EU MSs (Figure 8) [4].

From 2007 to 2011, Dombernowsky et al. reported a significant reduction (-3.9%) in the number of clinical trial applications (CTAs) in several EU Western countries. [36] Hartman observed a decrease in several countries, such as the Netherlands, Germany, France and the United Kingdom (1.9%, 2.3%, 3.0% and 5.3% average annually, respectively). This trend could be attributable to a variety of variables, including the EU CTD, local and national political decisions, and a potential global shift in clinical trial activity [37].

Since 2014, the number of CTAs in the old EU MSs increased significantly by 10% [36]. Considering the number of completed and ongoing clinical trials per 100,000 inhabitants (based on EUROSTAT data) in each EU Member State yields interesting findings (Figure 9) [22]. According to our results, Denmark ranks first (n = 56) for trials per 100,000 inhabitants followed by Belgium (n = 44), Austria (n = 33), Finland (n = 30) and the Netherlands (n = 30). The majority of EU-EECs, including Hungary, the Czech Republic, Lithuania and Bulgaria, fall between n = 29 and n = 33 trials per 100,000 inhabitants. These countries rank among the first eleven in the EU with the highest number of clinical trials conducted over the approximately 11-year period analyzed. Bulgaria ranks eleventh with (n = 29) trials per 100,000 inhabitants, ahead of nations with much larger populations, such as Spain (n = 17), Germany (n = 9), France (n = 7) and Poland (n = 11) (Figure 9).

Notwithstanding the greater increase in EU-EECs over the past decade, there has been a positive trend in the clinical research landscape of Western Europe, where 74% (n = 53185) of all EU completed and ongoing clinical trials were undertaken in the old EU MSs throughout the surveyed period.

Discussion

Advantages and challenges of conducting clinical trials in EU-EECs

In Central and Eastern Europe, the first prospective clinical trials in oncology were performed in the early 70s under the auspices of the Council of Mutual Economic Assistance (CMEA) [23].

The EU regulatory environment for conducting clinical trials to protect study subjects without prejudice to drug development is gradually evolving, together with all current EU and worldwide ICH standards in the field. It is expected that the introduction of the new EU Regulation (EC) 536/2014 with centralized single submission and approval will create a better clinical trial environment in the EU, improve opportunities and increase the interest in conducting clinical trials in the EU [2].

The indications are that the highest number of registered trials include oncology, rheumatology, cardiology, allergology and neurology. However, within all therapeutic categories, oncology indications predominate in EU-EECs and represent a substantial proportion of all ongoing trials in these countries [38].

Based on the survey, researchers conducted trials in the listed five countries in different Phases with the prevalence of Phase III up to 73.6%. Presumably the large patient population in the EU-EECs is one of the reasons for conducting such trials in these countries. Rare disease indications are also an option for conducting clinical trials in that region, which provides ideal possibilities for the sponsors to easily recruit patients. Pediatric trials have a share of up to 18.8% of all completed and ongoing studies in the five surveyed EU-EECs countries, which shows that there is enough experience with that delicate group of patients in these countries. Therefore, the EU-EECs is obviously a region where enrolling a patient with a rare disease or conducting pediatric trials might provide additional benefit for the sponsor. Bulgaria should be considered a desirable location for trials in this key domain because there is still a high number of unmet medical needs, and patients have limited access to many novel therapies.

Conducting clinical trials in Eastern European countries also offers the top investigators the opportunity to establish relationships with the worldwide medical community and publish their findings. In addition, it fosters the exchange of scientific knowledge regarding healthcare standards in EECs. The high productivity of sites in these countries is accompanied by regulatory compliance and data quality standards comparable to those in the EU’s western regions. Experienced professionals in this EU region have a high scientific interest and are very motivated in doing trials. These professionals work in large teams to publish new data about medical needs that are not being met and about which there is not enough information. Clinical trials could also be used as a basis for further scientific development at the academic level [38, 39].

Throughout the EU-EECs, there are many healthcare institutions, such as teaching university hospitals and clinics and postgraduate medical colleges. In Eastern European Union countries, teaching hospitals and university clinics employ many practising physicians as compared to their Western counterparts. According to EUROSTAT data, Bulgaria has 427 (per 100,000 inhabitants) directly practising physicians, whereas Germany has 458, Spain 447, and Hungary has 314 [39].

Any regulatory agency in the EU may inspect all clinical trials that are being conducted in the country. For the regulatory agency, the objective of the inspection is to collect evidence, evaluate the quality of a particular activity, and determine whether or not it complies with the existing regulatory requirements. CEE was one of the regions with the lowest percentage of inspections that required official or voluntary action, and the CEE sites are accompanied by regulatory compliance and data quality standards that are not inferior to those in Western regions. The percentages of inspections after which no follow-up action was indicated were 36.9% for Western Europe, 55.7% for CEE, and 44.3% for United States sites [38, 40].

An analysis of GCP inspections performed by the Good Clinical Practice (GCP) Inspectors Working Group (IWG) at the European Medical Agency between 2017 and 2022 showed a total of 381 inspections in support of the centralized procedure, of which 31.5% were carried out in the European Union (EU)/European Economic Area (EEA). Only 7.7% of all deficiencies discovered during the inspections were classified as critical, while 2.7% were analyzed as critical for the clinical investigator. The comparatively low number of critical findings suggests a higher level of GCP compliance since these findings are related to conditions, practices, or processes that adversely affect the rights, safety, or well-being of the subjects and the quality and integrity of data [41–42]. As these findings apply to the EU/EECs, they serve as evidence of high regulatory compliance.

Based on the study and several analyses for EU-EECs, the benefit and the reason why to conduct clinical trials in that region of EU might be listed as follows [38, 43–45]:

Reliability and predictability of regulatory timelines based on EC requirements;

Large patient population;

Different access to innovative medicines;

High number of medical staff per capita;

Experienced medical personnel willing to conduct clinical trials;

Experienced CRO personnel;

High recruitment potential (demonstrated by numerous trials in the study);

Distribution per all clinical Phases with the prevalence of Phase III;

Competitive cost per patient;

Low patient drop-out rates;

Clinical trials inspections with no inferior results to Western countries;

Experience in pediatric clinical trials.

There are many opportunities for pharmaceutical companies to undertake clinical trials with various patient demographics and rare disease indications in different phases. For such pharmaceutical companies, there are numerous advantages and benefits, including experienced site personnel, an EU member state with harmonized EU regulations for conducting high-quality clinical trials, and, last but not least, a cost-effective price. The scientific publications regarding the clinical trial advantages in EECs are limited, and future clinical trial sponsors might benefit from the data collected in this survey.

Substantial urban populations provide for faster enrolment and more effortless patient follow-up. These populations frequently regard clinical trials as credible healthcare options for accessing innovative complementary therapies and careful monitoring in specialized healthcare facilities, resulting in high patient retention rates. Furthermore, quality data is comparable to any other EU country and at a good value. Therefore, EU-EECs are a practical and straightforward solution for conducting global and EU clinical trials [38].

The present study also demonstrated that there is a high number of studies, which is obviously related to the high number of suitable and well-equipped sites performing clinical trials in Bulgaria. They are included in the Register for clinical trials in Bulgaria, published on the website of the Bulgarian Drug Agency [46].

There are also experienced and qualified investigators with a desire to be engaged in clinical trials for various reasons, i.e. reputation, professional growth and financial incentives. Our study demonstrated that the benefits of conducting clinical trials in EU-EECs and particularly in Bulgaria is obvious, with all advantages as presented and discussed in this paper.

Conclusions

The analysis performed in this study showed that the number of completed and ongoing trials is not solely dependent on the size of population of the country, but many other factors are involved. For all surveyed parameters in this study of five eastern EU countries, including Bulgaria, Hungary, Poland, Romania and Slovakia, and considering the number of trials per 100,000 inhabitants, the majority of clinical trials are concentrated in Hungary (n = 39) and Bulgaria (n = 29). The results indicate that Bulgaria is very advanced in clinical trials in EU-EECs, rating in the middle among all EU MSs (event place) taking into account the number of trials for the surveyed period. Based on the country population (100000 inhabitants) Bulgaria has similar results to Sweden and Slovakia and is ahead of many big EU western countries like Spain, France and Germany. This shows that the number of trials in Bulgaria has improved significantly due to many positive aspects. The study showed that of all trials included in the analysis (n = 19030) in total, the prevalence of Phase III studies was from 62.1% to 73.6%, of rare disease indication trials from 8.5% to 16.6%, and for pediatric trials from 15.3% to 18.8% among the five surveyed countries (Bulgaria, Hungary, Poland, Romania and Slovakia). The ongoing and completed clinical trials (n = 19030) conducted in all ten EU-EECs (from January 1, 2012 until September 30, 2022) have shown remarkable expansion over the last decade, accounting for a large portion (26.3%) of all EU ongoing and completed trials (n = 72215). The primary factors include the enhanced EU regulatory environment, well-trained medical staff, rapid recruitment, lower fees, and the sponsors’ acquisition of high-quality data. All these results proved that in the EU-EECs, there is good environment for attracting sponsors of clinical trials and conducting such trials. These clinical trials are additional therapy options and health resources for the healthcare systems in the EU-EECs, as well as a way to provide patients with access to innovative and new therapies that cannot be covered by the public budget funds.

Disclaimer

The views and opinions expressed in the article are those of the individual authors, they are not attributable to their employers and do not present any official view of any company or any department thereof.

Author contributions

T.B. study design and first draft of the manuscript; different parts of the analysis, literature searches and text order, final version of the analysis, linguistic check and journal requirements; D.M. data extraction from different clinical databases, figures, different parts of the analysis, literature searches and text order; V.K. different parts of the study analysis, linguistic check and journal requirements; I.I. and D.D. the data extraction from different clinical databases, figures, linguistic check and journal requirements; V.T., literature searches and text order; N.D. and I.C., different parts of analysis; L.T. different parts of analysis, final version of the analysis and the journal requirements; L.G. different parts of analysis and final version of the analysis. All authors have read and approved the final manuscript.

Data availability statement

Data are based on the EU Clinical Trials Register, which is open and data extraction is given under every figure and is under Reference [4] EU Clinical Trials Register, https://www.clinicaltrialsregister.eu

EUROSTAT. GDP per capita in PPS, https://ec.europa.eu/eurostat/databrowser/view/tec00114/default/table?lang=en

EUROSTAT. Total population of the European Union, https://ec.europa.eu/eurostat/cache/digpub/demography/vis/00_00_00/index.html?lang=en

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.